3-unsubstituted, 16-methylene pregnenes and pregnadienes



United States Patent ce 3,284,476 3-UNSUBSTITUTED, 16-METHYLENEPREGNENES AND PREGNADIENES Fred A. Kincl, Stockholm, Sweden, assignor toSyntex Corporation, Panama, Panama, a corporation of Panama No Drawing.Filed Oct. 22, 1965, Ser. No. 502,274

21 Claims. (Cl. 260--397.4)

This invention relates to novel cyclopentanopolyhydrophenanthrenederivatives and to processes for the preparation thereof.

More particularly, this invention relates to novel 3-desoxy-l6-methylenepregnenes and 3-desoxy-l6-methylenepregnadienesrepresented by the general formula:

In the above formula R represents hydrogen or methyl, R representshydrogen or a halogen having an atomic number less than 35, i.e.,fluorine or chlorine, R represents hydrogen or an acyl group, Rrepresents hydrogen, methyl, fluorine or chlorine, and Z representseither a double bond or a saturated linkage between C-6 and C-7.

The acyloxy and acyl groups referred to herein are preferably derivedfrom hydrocarbon carboxylic acids containing less than 12 carbon atomswhich may be saturated or unsaturated, of straight, branched, cyclic orcyclic-aliphatic chain, aromatic and may be substituted by functionalgroups such as hydroxy, alkoxy containing up to carbon atoms, acyloxycontaining up to 12 carbon atoms, nitro, amino or halogen. Typical estergroups are the acetate, propionate, enanthate, benzoate,trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate,am'inoacetate, and ,B-chloropr-opionate.

The novel 3-desoxy-16-methylenepregnenes and -pregnadienes representedby the above formula are progestationa-l agents having anti-estrogenic,anti-androgenic and anti-ovulatory properties, and thus are useful infertility control in humans and animals.

The novel compounds of the present invention are prepared by the processillustrated by the following equation:

3,284,476 Patented Nov. 8, 1966 (EH3 3 0:0 0:0 l

R R 0: HO

on a

I l l CH: OH: R R

III 5 I VH1 c 1HiR nitia 0:0 0:0 I --o l -o "0H, on, R R

1v 5 I IX 0a R4 l l (ILHgR (EH21?) 0:0 0:0 ()R: I"-OH I OH: TOE: R R

v i I X in 01'; R4 l rma 011,111 0:0 0:0 OR2 "-0112 FOE: l CH1 R R s o:l

XIII s XI In the above formulas R, R, R and R have the same meanings asset forth previously and R represents methyl, fluorine or chlorine.

Where fi-unsubstituted final products are desired, the starting materialI, i.e., A -pregnadien-313-01-20-0ne (I; R=methyl) or 19-nor-A-pregnadien-3;8-ol-20one (I; R=hydrogen; obtained as descried in mycopending U.S. patent application Serial No. 331,122, filed Dec. 17,1963), is subjected to Oppenauer oxidation, i.e., using aluminumisopropoxide in a mixture of toluene and cyclohexanone, to give thecorresponing A -3,20-dione, e.g., A -pregnadiene-3,20-dione (II;R=methyl). The latter compound, dissolved in a solution of diazomethanein diethyl ether, is allowed to stand at room temperature for about 24hours, followed by heating the solution at a temperature of about 180 C.or higher to decompose the initially formed 16,17-pyrazoline, thusgiving the corresponding 16-methyl-A -3,ZO-dione, that is, 16-methyl- A-pregnadiene-3,20 dione (HI; R=methyl). 'Ihe 16(17)-doub-le bond is thenselectively epoxidized to give the corresponding16B-methyl-16a,l7a-oxido steroid. This can be accomplished by any of anumber of methods known to the art. For example, hydrogen peroxide canbe admixed with a solution of the l6-methyl-A -3,20- dione in an inertorganic solvent, e.g., a lower alkonal, such as methanol or ethanol, anaromatic hydrocarbon such as benzene, toluene, or xylene, a chlorinatedhydrocarbon such as methylene dichloride, chloroform 0'1 carbontetrachloride, and the like, as well as mixture thereof, under alkalineconditions, e.g., in the presence of sodium hydroxide, at lowtemperature, e.g., about C. or lower, and the resulting reaction mixturecan then 'be allowed to stand at room temperature or lower, e.g., at 0C., overnight, to give the 16a,l7ot-0Xid0 intermediate.

Fluorine or chlorine can be introduced at the 2l-position immediatelyfollowing this expoxidation reaction, or after the 16a,17a-0Xld0 ringhas been cleaved to form the corresponding 16-methylene-17a-hydroxy or-acyloxy compound, or after a double bond has been introduced at the6(7)-position in said 16-methylene-17a-hydroxy or -acy1oxy compound, orafter the 3-keto group has been removed. In any event, the halogen atomcan be introduced by any of a number of methods known to the art.

Thus, for example, 16,8-methyl-l6a,l7a-oxidoA -pregnene-3,20-dione, canbe dissolved in an inert organic solvent, such as tetrahydrofuran or thelike, and then reacted with iodine in the presence of calcium oxide andmethanol at room temperature to give the corresponding 2l-iodointermediate, e.g., 21-iod0-16,8-methyl-16a,17a-oxido-A pregnene3,20-dione (IV: R=methyl, R=iodine). This 21-iodo intermediate can thenbe converted to the corresponding 21-fluoro compound, e.g.,21-fluoro-16f3-rnethyll6a,l7x -oxido-A -pregnene-3,20-dione (IV:R=methyl, R=fluorine), by reacting it at room temperature or below withsilver fluoride in aqueous acetonitrile solution.

Similarly, the 2l-iodo intermediate can be converted to thecorresponding 21-chloro compound, e.g., 21-chloro- 16/3 methyl16a,17a-oxido-A -pregnene-3,20-dione (IV: R=methyl, R=chlorine), bydissolving it in an inert organic solvent, e.g., dimethyl formamide orthe like, and then refluxing it for about 1 to 2 hours with lithiumchloride.

The l6a,l7-oxido moiety is cleaved to provide either the correspondingl6-methylene-17u-hydr0xy compound (V: R=methyl, R, R and R =hydrogen) ora l7-acylate thereof (V: R=methyl, R and R =hydrogen, R =acyl).

Whether a free 17a-hydroxy compound or a 17a-acyloxy compound isdesired, the cleaving reaction will take place in an inert organicsolvent of low ionizing power, e.g., an aromatic hydrocarbon such asbenzene, toluene or xylene, and ether such as diethyl ether, diisopropylether, dioxane or tetrahydrofuran, and the like, as well as mixturesthereof, in which the acid used is not freely ionized. This favors theformation of a high proportion of the 16- methylene compound.

To obtain the free 17ot-hydroxy compound, the cleaving reaction will becarried out at a temperature of from about 15 C. to about 30 C., andpreferably at room temperature, using either a strong mineral acid, suchas hydrochloric, hydrobromic, sulfuric or perchloric acid, or the like,or a strong carboxylic acid, such as formic, monochloroacetic,trifiuoroacetic, or the like. Thus, for ex ample, the oxido group in16B-methyl-l6a,l7a-oxido-A pregnene-3,20-dione can be cleaved to givel6-methylene- A -pregnen-17a-ol-3,20-dione (V: R=methyl, R, R and R=hydrogen), which can then be converted to the corresponding 21-fluoroor -chloro derivative. Alternatively, 2l-fiuoro (or-chloro)-16B-methyl-16a,l7a-oxido-A -pregnene-3,20-dione (IV: R=methyl,,R=fluorine or chlorine) can be similarly reacted to cleave the oxidogroup to give 21-fluoro (or chloro)-16-methylene-A -pregnen-17a-ol-3,20-dione (V: R=methyl, R=fluorine or chlorine, R and R=hydrogen).

The corresponding 17a-acyloxy compound can be obtained by carrying outthe cleaving reaction at a temperature of from about 20 C. to about C.using an acid anhydride, preferably an anhydride of a hydrocarboncarboxylic acid containing less than 12 carbon atoms as describedhereinabove, in the presence of an acid catalyst, e.g.,p-toluenesulfonic acid or the like, followed by acid hydrolysis toselectively remove the 3-enol acylate grouping and regenerate the A-3-keto system. Thus, for example, by reacting 16flmethyl-16a,l7a-oxido-A -pregnene-3,20-dione with acetic anhydride in thepresence of p-toluenesulfonic acid at about 100 C. and then reacting atlow temperature, e.g., 05 C., with methanolic potassium hydroxide or thelike in dioxane, tetrahydrofuran or the like, 16-methylene-A-pregnen-l7a-ol-3,20dione 17 acetate (V: R=methyl, R and R =hydrogen, R=acetyl) is obtained, and can then be converted to the corresponding2l-fluoro or -chloro derivative, while 21- fluoro- (or-chloro)-16;3-methyl-l6a,17aoxido-A -pregnone-3,20-dione (IV: R=methyl,R =fluorine or chlorine), by the same treatment, gives 2l-fiuoro (or-chloro)- 1G-methylene-M-pregnen-l7u-ol-3,20-dione l7-acetate (V:R=methyl, R=fiuoro or chloro, R =acetyl, R =hydrogen).

It is preferred that the cleaving reaction be carried out so as to givethe 17-ester, which, after the 3-keto group has been removed to give the3-desoxy-A or A -final product, can then be hydrolyzed to thecorresponding free 17a-ol, if desired, by boiling with a 1-5 aqueousmethanolic solution of sodium hydroxide or potassium hydroxide for fromabout 2 to 24 hours under an inert nitrogen atmosphere.

The l7-acylates can also be prepared either directly after cleaving thel6u,l7a-oxido group to give a free 170:- hydroxy compound, after theintroduction of a 6(7)- double bond, or after the removal of the 3-ketogroup, from the corresponding l7ot-hydroxy compounds by directacylation, e.g., by using a mixture of a hydrocarbon carboxylic acid ofthe type described hereinabove and the corresponding anhydride, such asa mixture of acetic acid and acetic anhydride, in the presence of anacid catalyst such as p-toluenesulfonic acid or the like. This gives theA -3,17-diacylate, from which the enol acylate group can be removed andthe A -3-keto system regenerated in the manner described hereinabove.

As previously indicated, when introducing fluorine r chlorine at the21-position at any point after the 16a,17x oxido ring has been cleaved,the same procedures as those described hereinabove for fiuorinating orchlorinating the Zl-carbon atom in the 16u,17ot-OXiClO intermediate canbe used. However, a fluorine or chlorine atom can also be introduced atthe 2l-position in a l6-methylene- M-pregnen-l7a-0l-3,20-dione by firstpreparing the corresponding 21-iodo derivative, e.g., by reaction withiodine at room temperature in the presence of calcium oxide andmethanol, then refluxing this 2l-iodo intermediate with freshly fusedpotassium acetate in acetone for about 8 hours or longer to form thecorresponding 21-acetoxy derivative, next saponifying this 21-acetate byconventional means, e.g., by refluxing with aqueous methanolic sodiumhydroxide, potassium hydroxide, potassium carbonate, or the like, togive the corresponding free 21- hydroxy compound, then forming thecorresponding 2l-mesylate by reacting the free 2l-hydroxy compound forabout 24 hours or longer with mesyl chloride in pyridine, and finallyrefluxing the thus-obtained 21- rnesylate with silver fluoride inaqueous acetonitrile for from about 15 minutes to about 24 hours to givethe Zl-fluoro compound, or with lithium chloride in dimethylformamidefor from about 1 to about 2 hours to give the corresponding 2l-chlorocompound.

Where 6-substituted final products are desired, the (6)-double bond inthe starting material I is selectively epoxidized in known manner, e.g.,using a peracid such as monoperphthalic acid, perbenzoic acid, or thelike, preferably in excess, in an inert organic solvent, e.g., achlorinated hydrocarbon such as methylene dichloride, chloroform orcarbon tetrachloride, an ether such as diethyl ether, diisopropyl ether,or the like, as well as mixtures thereof, and preferably a mixture ofchloroform and diethyl ether, at room temperature for from about 1 toabout 60 hours to give the corresponding 50,6mepoxide, i.e.5a,6a-oxido-A -pregnen-3fi-ol-ZO-one.

The ZO-keto group is then ketalized in known manner, e.g., using a loweralkylene glycol such as ethylene glycol, propylene glycol, or the like,in the presence of a small amount of an acid catalyst such asp-toluenesulfonic acid or the like, thus giving the correspondingZO-ketal, e.g., 20-cycloethylenedioxy-5a,6a-oxido-A pregnen-3B-ol.

Alternatively, the starting material I can first be ketalized, thusgiving, for example, 20-cycloethylenedioxy- A -pregnadien-3B-ol, andthis 20-ketal can then be epoxidized to give the corresponding5a,6ot-oxido steroid, e.g., 20-cycloethylenedioxy-5a,6ot-oxido-A-pregnen-3;?- ol, each of these reactions being carried out in themanner described hereinabove.

In preparing 6-methyl compounds, the thus-obtained5a,6ot-'OXidO-20-k6'f3.1 intermediate is refluxed with methylmagnesiumbromide in tetrahydrofuran, thus giving the corresponding5ot-hydroxy-6B-methyl intermediate, e.g.,

20 cycloethylenedioxy 6p methyl A pregnene- 3fi,5oc-di01 (VI: R and R=methyl).

In preparing 6-fluoro or -chloro compounds, the 50,6aoxido-20-ketalintermediate is reacted with boron trifluoride in a mixture of diethylether and benzene, or with anhydrous hydrogen chloride in chloroform, togive the corresponding 5a-hydroxy-6B-fluor-o or -chloro intermediate,e.g., 20 cycloethylenedioxy 6B fluoro (or -chloro) A pregnene 35,50;diol (VI: R=methyl, R fluorine or chlorine).

The thus-obtained 5ot-hydroxy-6B-substituted intermediate is thenhydrolyzed in known manner, e.g., using a strong acid such as 8%sulfuric acid in methanol, concentrated hydrochloric acid in acetone, orthe like, thus giving the corresponding free 20-keto steroid, e.g.,6/3-methy1 (-fiuoro or -chloro)-A -pregnene,3fl,5a-diol- 20-one (VII:R=methyl, R =methyl, fluorine or chlorine).

The 16-methyl group is then introduced by reacting the5ot-hydroxy-6B-substituted-20-one with diazomethane in diethyl ether inthe manner described hereinabove to give the corresponding16-methyl-6fl-substituted-A steroid, i.e., 65,16-dimethyl Apregnene-3/3,5a-diol-20- one (VIII: R and R =methyl).

Epoxidation of the l6(l7)-double bond in this 66- substituted-l6methyl-A-steroid, using alkaline hydrogen peroxide in the manner describedhereinabove, gives the corresponding6/3-substituted-l6/3-methyl-16u,17a-oxido steroid, e.g.,6e,16B-dimethyl-l6u,17ot-oxidopregnane- 3fi,5a-diol-20-one (IX: R and R=methyl, R'=hydrogen).

Fluorine or chlorine can be introduced at the 2l-position immediatelyfollowing this epoxidation reaction, or after the 16oc,17ot-'0Xid0 ringhas been cleaved to form the correspondingl6-methylene-6B-substituted-17e-hydroxy compound, or after the A -3-ketosystem or a 6(7)- double bond has been introduced, or after the 3-ketogroup has been removed, and in all cases, the procedures describedhereinabove can be used to accomplish this.

The epoxy group in the 6,8-substituted-l6a,l7a-oxido steroid is cleavedwith a strong mineral or organic acid in the manner describedhereinabove to give the correspondingl64methylene-6fi-substituted-17a-hydroxy compound, e.g.,16-methylene-6fl-methylpregnane-3fl,5a,17atriol-ZO-one (X: R and Rmethyl, R'=hydrogen).

By oxidizing the thus-obtained 16-methylene-6f3-substituted-l7a-hydroxycompound with 8 N chromic acid in acetone solution, the corresponding16-methylene-6asubstituted-A -3-one, e.g., l6-methylene-6u-methyl'Apregnen-l7a-ol-3,20-dione (V: R and R=methyl, R and R zhydrogen).

The corresponding l7-acylates can be prepared by direct acylation in themanner described hereinabove, followed by selective hydrolysis to removethe 3-acyl group and regenerate the A -3-keto system, and the acylationreaction can also be carried out after the introduction of a 6(7)-doublebond or the removal of the 3-keto group. Thus, for example, acylation ofl6-methylene- Ga-methyl-M-pregnen-l7a-ol-3,20-dione with a mixture ofacetic anhydride and acetic acid in the presence of p-toluenesulfonicacid, followed by selective hydrolysis with methanolic potassiumhydroxide, gives the corre sponding l7-acetate (V; R and R =methyl,R=hydrogeu, R =acetyl).

In the next step of the process as outlined hereinabove, the16-methylene-6a-substituted or -unsubstituted-17ot-hydroxy or -acyloxy-A-3-one V, and preferably a 17-acylate, e.g., 16-methylene-A-pregnen-l7a-ol-3,20-dione 17- acetate, is converted to thecorresponding B-dithioketal, i.e., 3-cycloethylenedithio-l6-methylene-A-pregnen-17aol-20-one 17-acetate (XI; R=methyl, R and R =hydrogen, R=acetyl), by reacting it with ethanedithiol in glacial acetic acid atroom temperature for from about 30 minutes to about 30 hours.

7 Next, the resulting 3-dithioketal, dissolved in a lower alkanol suchas methanol, ethanol, or the like, is reacted with Raney nickel at atemperature of from about 15 C. to about 120 C. for from about 1 toabout 30 hours, thus giving the corresponding 3-desoxy-l6-methylene-Apregnene, e.g., 16 methylene-A -pregnen-17a-ol-20-one l7-acetate (XII;R=methyl, R and R =hydrogen, R =acetyl).

The corresponding 3-desoxy-l6-methylene-A -pregnadienes can be preparedby first reacting the 16-methylene-17ot-hydroxy or -acyloxy steroid (V)with chloranil in t-butanol, thus giving the corresponding 6-dehydroderivative, e.g., 16-methylene-A -pregnadien-l7a-0l-3,20 dione17-acetate (XIII; R=methyl, R and R =hydrogen, R =acetyl).

This A -diene is then reacted with ethanedithiol in the manner describedhereinabove to give the corresponding 3-dithioketal, e.g., 3-cycloethylenedithio-l6-methylene- A -pregnadien-17a-ol-20-one17-acetate (XIV; R=methyl, R and R =hydrogen, R =acetyl), which is thenreacted with Raney nickel in the manner described hereinabove to givethe corresponding 3-desoxy-16-methylene- A -pregnadiene, e.g.,l6-methylene-A -pregnadien-17aol-20-one 17-acetate (XV; R=methyl, R andR =hydrogen, R =acetyl).

The 3-desoxy-l6-methylene-A -pregnadienes having a 6-fiuoro or -chlorosubstituent can also be prepared by a process which can be illustratedschematically as follows:

---on '---0R CH1 :CII n n xvr XVII 311m ornn 0:0 0:0 om ore I CH: I OH:R R

0: s XIX XVIII JHIR o=o Y XX In these formulas R, R and R have the samemeanings as set forth previously, and R represents fluorine or chlorine.

In carrying out this process a 6-unsubstituted-6-dehydro steroid, e.g.,16-methylene-A* -pregnadien-17a-ol-3,20- dione 17-acetate (XVI;R=methyl, R'=hydrogen, R

acetyl) is reacted with a peracid in the manner described hereinabovefor the preparation of the Sa,6u-oxido intermediate to give thecorresponding 6a,7a-oxido intermediate, e.g., 6a,7a-oxido-l6-methylene-A-pregnen-l7ot-ol- 3,20-dione 17-acetate (XVII; R=methyl, R'=hydrogen, R=acetyl).

A 6-fiuoro substituent is introduced by reacting the thusobtained6a,7a-oxido steroid with boron trifluoride in a mixture of diethyl etherand benzene, preferably at room temperature overnight, to form thecorresponding 65- fiuoro-7cw'hydroxy intermediate, which can then bedehydrated to remove the 7a-hydroxy group and reintroduce a 6(7)-doublebond by suspending it in glacial acetic acid and passing a current ofhydrogen chloride gas through the suspension at room temperature orbelow, e.g., at from about 15 C. to about 25 C., for from about 2 to 6hours, thus giving the corresponding 6-fluoro-6- dehydro steroid, e.g.,6-fiuor0-l6-methylene-A -pregnadien-17a-ol-3,20-dione l7-aceta-te(XVIII; R=methyl, R'=hydrogen, R acetyl, R =fluoro).

A 6-chloro substituent can be introduced by treating the 60,7ot-0Xid0intermediate with anhydrous hydrogen chloride in an inert solvent suchas acetic acid at a temperature from about 15 C. to 25 C. for a periodof time from 3 to 12 hours to produce the corresponding 6-chloro-6-dehydro compound.

The resulting 6-fluoro or -chloro-6dehydro steroid is then converted tothe 3-dithioket-al (XIX) in the manner described above, following whichtreatment with Raney nickel in the manner described hereinabove givesthe 3-desoxy-6-fluoro or -chloro-l6 methylene-A -pregnadiene (XX).

In order that those skilled in the art can more fully understand thepresent invention, the following examples are set forth. These examplesare given solely for the purpose of illustrating the invention, andshould not be considered as expressing limitations unless so set forthin the appended claims.

EXAMPLE I One gram of A -pregnadien-3fl-ol-20-one was dissolved in amixture of 30 cc. of commercial grade xylene and 10 cc. ofcyclohexanone, and 10 cc. of this solvent mixture were then distilledoff to remove moisture. Next, a solution of 1 gram of aluminumisopropoxide in 5 cc. of anhydrous xylene was added dropwise, over a 5minute period, to the slowly distilling solution, and distillation wasthen continued following this addition for 45 minutes. The solventmixture was then removed by steam distillation, and the resulting solidwas collected by filtration on Celite, washed with water and dried.Extraction of the dry solid with hot acetone, followed byrecrystallization from acetone, gave A -pregnadiene-3,ZO-dione.

By repeating this procedure in every detail but one, namely, replacing A-pregnadien-3/3-ol-20-one with 19- nor-A -pregnadien-3/3-ol-20-one asthe steroid starting material, l9-nor-A -pregnadiene 3,20-dione wasobtained.

EXAMPLE II One gram of A -pregnadiene-3,20-dione was dissolved in 30 cc.of a 1 N solution of diazomethane in diethyl ether, and the resultingreaction mixture was then allowed to stand at room temperature for 24hours. Following this reaction period 5 cc. of acetic acid were added todestroy excess diazomethane, and the solvent was then evaporated underreduced pressure to give the dry, crude 16a,17a-pyrazoline, which wasthen decomposed by heating it gradually to C. under vacuum.Recrystallization of the resulting solid product from acetone/hexanegave 16-Inethyl-A -pregnadiene-3,20-dione.

By repeating this procedure using 19-nor-A -pregnadiene-3,20-dione asthe steroid starting material, 16-methyl-19-nor-A-pregnadiene-3,20-dione was obtained.

9 EXAMPLE In A solution of 5 grams of 16rnethyl-A -pregnadiene-3,20-dione in 150 cc. of methanol was cooled to 15 C. Next, 20 cc. of anaqueous 4 N solution of sodium hydrox-ide and 20 cc. of 30% hydrogenperoxide were added, with stirring, the temperature being maintained at15 C. during this addition. The resulting reaction mixture was allowedto stand at C. overnight, then poured into ice water. The resultingprecipitate was collected by filtration, washed with water until neutraland dried. Recrystallization from acetone/hexane gave 165-methyl-16a,17a-oxido-A -pregnene,20-dione.

By repeating this procedure using 16-methyl-19-nor- A-pregnadiene-3,20-dione as the steroid starting material, 165-methyl19-11OY-160t,170t oxido-A -pregnene- 3,20-dione was obtained.

EXAMPLE IV A cooled, continuously stirred solution of 5 grams of 165methyl 1604,17oc oxido A pregnene 3,20- dione in a mixture of 30 cc. oftetrahydrofuran and 18 cc. of methanol was treated first with 6 grams ofcalcium oxide, added in small portions, and then with 6 grams of iodine.The resulting reaction mixture was then stirred at room temperatureuntil it turned pale yellow. At this point the reaction mixture waspoured into ice water containing 18 cc. of acetic acid and 2 grams ofsodium thiosulfate and, after stirring for 15 minutes, the solution wasdecanted and the precipitate collected by filtration, washed with waterand dried under reduced pressure, thus giving 21 iodo 165 methyl1606,1706- oxido-A -pregnene-3,20 dione.

This 21-iodo intermediate was then dissolved in 20 cc. of acetonitrile.To this solution there was added dropwise 1.4 grams of silver fluoridedissolved in 3 cc. of water. After a short time, silver iodide began toprecipitate, leaving the desired 21-fluoro steroid in solution. Thereaction mixture was allowed to stand for 24 hours at room temperature,then filtered. Concentration of the filtrate under reduced pressure gavea crude product which, after crystallization from acetone/methanol, gave21-fluoro- 165-methy1-16a, l7a-oxido-A -pregnene-3,20-dione.

By repeating this procedure using 165 methyl 19- nor 16a,l7oc oxido Apregnene 3,20 dione as the steroid starting material, the corresponding21-iodo intermediate, followed by 21 fiuoro 165 methyl 19-nor-16a,17a-oxido-A -pregnene-3,20-dione, was obtained.

EXAMPLE V A suspension of 10 grams of lithium chloride in 50 cc. ofdimethylformamide was heated to boiling. Next, a solution of 2 grams of21 iodo 165 methyl 1604,1711- oxido A pregnene 3,20 dione in 10 cc. ofdimethylformamide was added, and the resulting reaction mixture wasrefluxed for 2 hours. Following this reaction period the reactionmixture was cooled and poured into water, and the thus-formedprecipitate was filtered off and crystallized from acetone/ hexane togive 21 chloro 165- methyl-16a,17ot-oxido-A -pregnene-3,20-di0ne.

By repeating this procedure using 21 iodo 165- methyl 19 nor 16ot,17aoxido A pregnene 3,20- dione as the steroid starting material,21-chloro-165- methyl 19 nor 16oc,17rx oxido A pregnene 3,20- dione wasobtained.

EXAMPLE VI A mixture of 1.2 grams of 165 methyl l6oc,17otoxido Apregnene 3,20 dione, ml. of trifluoroacetic acid and 10 ml. of benzenewas allowed to stand at room temperature for 2 hours. Following thisreaction period water was added to the reaction mixture, and theresulting solution was extracted with methylene dichloride. The organicextract was washed with an aqueous 5% potassium bicarbonate solution,then with a satu- 10 rated sodium chloride solution, and then dried overanhydrous magnesium sulfate. Crystallization from acetone/diethyl ethergave 16 methylene A pregnen- 17a-ol-3,20-dione.

This procedure was then repeated using 21-fiuoro-165- methyl 1605,1706oxido A pregnene 3,20 dione, 21 chloro methyl 1604,1711 oxido A pregnene3,20 dione, 165 methyl 19 nor 16a,17uoxido A pregnene 3,20 dione, 21fiuoro 165- methyl 19 nor 16ec,170z oxido A pregnene 3,20- dione, and 21chloro 165 methyl 19 nor 16u,17uoxido A pregnene 3,20 dione,respectively, as the steroid starting material. In each case, thecorresponding 16 methylene steroid, namely, 21 fiuoro l6 methylene Apregnen a ol 3,20 dione, 21 chloro- 16 methylene A pregnen 17a ol 3,20dione, 16 methylene 19 nor A pregnen 17oz o1 3,20- dione, 21 fluoro 16methylene 19 nor A pregnen 17a o1 3,20 dione, and 21 chloro l6 methylene19 nor A pregnen 17oz o1 3,20 dione, respectively, was obtained.

EXAMPLE VII One gram of p-toluenesulfonic acid monohydrate, 50 cc. ofacetic acid and 25 cc. of acetic anhydride were added to 1 gram of 16methylene A pregnen 17aol-3,20-dione, and this reaction mixture was thenallowed to stand at room temperature for 24 hours. Following thisreaction period the reaction mixture was poured into water and stirredto hydrolyze excess acetic anhydride, then extracted with methylenedichloride. The thus-obtained extract was washed with an aqueous 5%sodium bicarbonate solution and then with water until neutral, thenevaporated to dryness under reduced pressure. Recrystallization fromacetone/diethyl ether gave 16-methyleneA pregnadiene 3,17u diol 20 one3,17 diacetate.

The thus-obtained enol acetate was dissolved in a mixture of 15 cc. ofmethanol and 3 cc. of tetrahydrofuran, cooled to 0 C., and then admixedwith 5 cc. of a 2% methanolic potassium hydroxide solution which hadpreviously been cooled to 0 C. The resulting reaction mixture was heldat 0 C. for 1 hour, then poured into water and neutralized with dilutehydrochloric acid. Next, the neutral solution was extracted with diethylether, and the thus-obtained amorphous product was chromatographed onethyl acetate-washed alumina. The hexane/ benzene (1:3, respectively, byvolume) eluates gave a product which was recrystallized fromacetone/hexane, thus giving 16 methylene A pregnen 17a ol 3,20- dione17-acetate.

By repeating this procedure using mixtures of propionic acid andpropionic anhydride, caproic acid and caproic anhydride, and enanthicacid and enanthic anydride, respectively, in place of acetic acid andacetic anhydride, the corresponding 17-propionate, -caproate and-enanthate were obtained.

Similarly, by repeating this procedure using the remaining16-methylene-17a-hydroxy steroids prepared as described in Example VIhereinabove as the steroid starting materials, the corresponding17-acetates were obtained.

EXAMPLE VIII To a solution of 1 gram of 165-methyl-16a,17a-oxido- Apregnene-3,20-dione in 10 ml. of benzene there were added, withstirring, 5 ml. of acetic anhydride and 0.1 gram of p-toluenesulfonicacid. The resulting reaction mixture was heated to 100 C. and maintainedat that temperature for 15 minutes, with continuous stirring, followingwhich it was cooled, poured into Water and stirred to hydrolyze excessacetic anhydride and precipitate the product. The precipitate Wascollected by filtration, washed with water, dried and then crystallizedfrom aqueous methanol containing a trace of pyridine, thus giving 16methylene A -pregnadien-3,17u-diol-20-one 3,17-diacetate, identical tothe first product prepared as described in Example VII hereinabove.

EXAMPLE IX A solution of 2.5 grams of A -pregnadien-3fi-ol-20- one in100 cc. of chloroform was cooled to C. and admixed with a solution of1.1 molar equivalents of monoperphthalic acid in 100 cc. of diethylether, and the resulting reaction mixture was then allowed to stand atroom temperature for 20 hours. Following this reaction period thereaction mixture was diluted with water and the organic layer wasseparated, washed with an aqueous sodium bicarbonate solution and thenwith water until neutral, then dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization of the resulting residue fromacetone/hexane gave 5a,6u-oxido-A -pregnen-3fl-o1-20-one.

By repeating this procedure using 19-nor-A -pregnadien-3/8-ol-20-one asthe steroid starting material, 19-nor- 5a,6u-oxido-A-pregnen-3p-ol-20-one was obtained.

EXAMPLE X A mixture of 1 gram of 5a,6u-oxido-A -pregnen-3/3-01- -one,cc. of anhydrous benzene, 5 cc. of ethylene glycol and 50 mg. ofp-toluenesulfonic acid monohydrate was refluxed for 16 hours, using awater separator to remove the water formed during the reaction.Following this reaction period the reaction mixture was washed with anaqueous 5% sodium bicarbonate solution and then with water, then driedover anhydrous sodium sulfate and evaporated to dryness under reducedpressure. Recrystallization from acetone/ hexane gave20-cycloethylenedioxy- 504,6a-oxido-A -pregnene-3B-ol.

By repeating this procedure using 19-I10f-5ot,6oz-OXiClO- A-pregnen-3/3-ol-20-one as the steroid starting material, 20cycloethylenedioxy-19-nor-5u,6a-oxido-A -pregnen- 36-01 was obtained.

EXAMPLE XI A solution of 5 grams of 20-cycloethylenedioxy-S04,604-oxido-A -pregnen-3/3-ol in 200 cc. of tetrahydrofuran was cooled to 0 C.and then treated with 1.5 molar equivalents of methylmagnesium bromidedissolved in 100 cc. of diethyl ether. The resulting reaction mixturewas refluxed for 2 hours, then cooled to room temperature. Next, Waterwas added to the reaction mixture and the product was isolated byextraction with diethyl ether. The thus-obtained extract was admixedwith 100 cc. of an aqueous methanolic 2% sodium hydroxide solution,following which it was washed with water until neutral, dried overanhydrous sodium sulfate and evaporated to dryness. Recrystallizationfrom methylene dichloride/ hexane gave 20-cycloethylenedioxy 6,8methyl-A -pregnene-3fl,5a-diol.

By repeating this procedure using20-cycloethylenedioxy-19-nor-5a,6a-oxido-A -pregnen-3fi-ol as thesteroid starting material, 20 cycloethylenedioxy 6B methyl-l9- nor-A-pregnene-3,B,5a-diol was obtained.

EXAMPLE XII Five cc. of freshly distilled boron trifiuoride etheratewere added to a solution of 5 grams ofZO-cycloethylenedioxy-5u,6a-oxido-A -pregnen-3{3-01 in a mixture of 250cc. of diethyl ether and 250 cc. of benzene, and the resulting reactionmixture was allowed to stand at room temperature overnight. Followingthis reaction period water was added to the reaction mixture and theorganic layer was separated, washed with water until neutral, dried overanhydrous sodium sulfate and evaporated to dryness under reducedpressure. Recrystallization of the resulting residue from methylenedichloride/hexane gave 20-cycloethylenedioxy-6fl-fiuoro-A-pregnene-3[3,5a-diol.

By repeating this procedure using20-cycloethylenedioxy-19-nor-5a,6a-oxido-A -pregnen-313-01 as thesteroid starting material, ZO-cycloethylenedioxy-6/3-fluoro-l9-nor- A-pregnene-lififiu-diol was obtained.

12 EXAMPLE XIII Thirty cc. of a 0.45 N solution of dry hydrogen chloridein chloroform were added, with stirring, over a 35 minute period, to asolution of 4 grams of 20-cycloethylenedioxy-5a,6a-oxido-A-pregnen-3B-o1-2O-one in 40 cc. of chloroform, the temperature of thereaction mixture being maintained at about 0 C. during this addition.Following the addition of the last of the hydrogen chloride solution thereaction mixture was stirred at 0 C. for one hour more, then dilutedwith water. The chloroform layer was separated, washed with an aqueous5% sodium bicarbonate solution and then with water until neutral, thendried over anhydrous sodium sulfate and evaporated to dryness underreduced pressure. Crystallization of the resulting residue fromacetone/hexane gave 6;? chloro 20 cycloethylenedioxy Apregnene-3[3,5a-diol.

By repeating this procedure using 19-nor-'5a,6z-oxido- A -pregnen-3fi-olas the steroid starting material, 6,8- chloro 20 cycloethylenedioxy 19nor A pregnene-3fi,5a-diol was obtained.

EXAMPLE XIV A solution of 2 grams of ZO-cycloethylenedioxy-6flmethyl-A-pregnene-3B,5a-diol in 70 cc. of methanol was admixed with 7 cc. ofaqueous 8% sulfuric acid, and the resulting reaction mixture wasrefluxed for 40 minutes. Following this reaction period the reactionmixture was neutralized by the addition of a saturated sodium carbonatesolution, then concentrated under reduced pressure to a volume of about20 cc. and poured into water. The thus-formed precipitate wa collectedby filtration, washed with water and dried. Recrystallization fromacetone gave 6B-methy1-A -pregnene-3p,5u-diol-20-one.

By repeating this procedure using 20-cycloethylenedioxy-6fl-fluoro-A-pregnene-3 5,5 a-diol, 6,8-chloro-20-cycloethylenedioxy-A-pregnene-35,5a-diol, 2O-cycloethylenedioxy-6fl-methyl-19-nor-A-pregnene- 3 3,5 u-diol, 20-cycloethylenedioxy-6fl-fluoro-19-nor-A-pregnene- 3 5,5 a-diol, and 6/3-chloro-20-cycloethylenedioxy-19-nor-A-pregnene- 313,5 oc-diOl,

respectively, as the steroid starting material, the correspondlng20-keto steroids, namely,

6 8-fluoro-A -pregnene-iifi,5a-diol-20-one, 6/8-chloro-A-pregnene-3{3,5a-diol-20-one, 6,6-methyl-19-nor-A -pregnene-36,5u-diol-2O-one, 6fl-fiuoro-19-nor-A -pregnene-3B,5a-diol-20-one, and6/3-chloro-l9-nor-A -pregnene-3p,5a-diol-20-one, respectively, wereobtained.

EXAMPLE XV The procedure of Example II hereinabove was repeated usingthe 20-keto steroids prepared as described in Example XIV hereinabove asthe steroid starting material. In each case, the corresponding16-methyl-A -steroid, namely,

6B,16-dirnethyl-A -pregnene-3fi,5a-diol-2O-one, 6B-fiuoro-16-methyl-A-pregnene-3B,5a-diol-20-one, opt-chloro-16-methyl-A-pregnene-3B,5a-diol-20-one, 6B,1G-dimethyl-19-nor-A-pregnene-3,B,5at-diol-20-one, 6B-fluoro-16-methyl-l9-nor-A-pregnene-3fl,5a-diol-20- one, and 6,8-chloro-16-methyl-19-nor-A-pregnene-3p,Sa-diol- 20-one,

respectively, was obtained.

EXAMPLE XVI The 16(17)-double bond in the 16-methyl-A -steroids preparedas described in Example XV hereinabove was epoxidized in the mannerdescribed in Example III hereinabove, thu giving65,165-dimethy1-1604,1704-oxidopregnane-35, 504-diol- 20-one,65-fiuoro-l65-methyl-1604,1704-oxidopregnane-35,504-

diol-ZO-one, I 65-chloro-l65-methyl-1604,1704-oxidopregnane-35,504-

diol-20-one, 65,165-dimethyl-19-nor-1604,1704-oxidopregnane-35,504-

diol-20-one, 65fluoro-165-methyl-19-nor-l604,1704-oxidopregnane- 35,504-diol-20-one, and65-chloro-l65-methyl-19-nor-1604,1704-oxidopregnane- 35, 504-diol-20-one, respectively.

EXAMPLE XVII The 1604,1704-oxido steroids prepared as described inExample XVI hereinabove were treated in the manner described in ExampleIV hereinabove to give first the corresponding 21-iodo steroids, namely,65,l65-dirnethyl-21-iodo-1604,1704-oxidopregnane-35,504-

diol-ZO-one, 65-fluoro-21-iodo-165-methyl-1604,1704-oxidopregnane-35,504-diol-20-one,65-chloro-2l-iodo-165-metl1yl-l6o4,l7o4-oxidopregnane-35,504-diol-20-one,65,165-dimethyl-2l-iodo-19-nor-1604,1704-oxido-pregnane-35,504-diol-20-one,65-fluoro-2l-iodo-l65-methyl-19-nor-l6o4,l7o4-oxidopregnane-35,504-diol'-20-one,and65-chloro-21-iodo-165-methyl-19-nor-1604,17o4-oxidopregna11e-35,504-diol-20-one,

respectively, and then the corresponding 21-fluorosteroids, namely,

65,165-dimethyl-21-fluoro-1604,1704-oxidopregnane- 3 5,504-diol-20-one,65,21-difluoro-165-methyl-1604, l7o4-oxidopregnane- 35,5 04-diol-20-one,65-chloro-2l-fluoro-165-methyl-1604,1704-0xidopregnane- 3 5,504-diol-2O-one,65,165-dimethyl-21-fluoro-19-nor-1604,1704-oxidopregmane-35,504-diol-20-one,65,2l-difiuoro-165methyl-19-nor-1604,1704-oxidopregmane-35,504-diol-20-one, and65-chloro-21-fiu0ro-l65-methyl-19-nor-1604,1704-oxidopregnane-35,504-diol-2O-one,respectively.

EXAMPLE XVIII The 21-iodo steroids prepared as described in Example XVIIhereinabove were treated in the manner described in Example Vhereinabove, thus giving the corresponding 2l-cl1lono steroids, namely,

VI hereinabove, thus giving the corresponding 16-met'hy1 ene-1704-ols,namely,

16-methylene-65-methylpregnane-35,504,1704- *triol-ZO-one,65-fluoro-16-rnethylenepregnane-35,504,1704- triol-ZO-one, 65-chloro-l6-met-hylenepregnane-35,504,1704- triol-20-one, l6-methylene-65-methyl-19-norpregnane-35,54x,1704- tri0l-20-one,65-fluoro-16-methylene-19-norpregnane-35,504,1704- triol-20-one,65-chloro-16-rnethylene-19-norpregnane-35,504,1704- tri0l-20-one, 2l-fiuoro-l 6 methylene-65-methylpregnane-35,504,1704- triol-20-one,65,21-difiuoro-l 6-methylenepregnane-35,504,1704- triol-ZO-one,65-chloro-21-fluoro-l6-methylenepregnane-35,504,1704- triol-ZO-one,21-fiuoro-l-6-methylene-65-methyl-19-norpregnane- 35,5 04,1704-triol-20-one, 65,21-difiuoro-16-methylene-l9norpregnane- 3 5,5 0t,l704-triol-2 O-one, 6 5-chloro-2 1 -fluorol 6-methylene-1 9-norpregnane- 3 5,504- l 704-triol-20-one, 2 l -chloro-1 6-methylene-65-methylpregn ane- 3 5,504, 1704-triol-2O-one,2l-chloro-65-fluoro-16-methylenepregnane- 3 5,5 04, 1704-triol-20-one,65,21-dichloro,16-methylenepregnane- 3 5,5 04, 1704-triol20-one,65-methyl-21-chloro-16-methylene-l9-norpregnane-35,504,1704-triol-20-one,21-chloro-65-fluoro,1-methylene-19-norpregnane- 3 5,5 04,1704-triol-20-one, and 65,21-dichloro-1'6-rnethy1ene-19-norpregnane- 35,504,1704-triol-20one,

EXAMPLE XX A solution of 1 gram of16-methylene-65-methylpregnane-35,504,1704-triol-20-one in 10 cc. ofacetone was cool d to 0 C. and then admixed under an inert nitrogenatmosphere, with stirring, with an 8 N chromic acid solution (preparedby mixing 26 grams of chromium trioxide with 23 cc. of concentratedsulfuric acid and diluting with water to give cc. of solution), the acidsolution being added until its color persisted in the reaction mixture.Following this addition the reaction mixture was stirred for anadditional 5 minutes at 05 C., then diluted with water. The resultingprecipitate was collected by filtration, washed with water and driedunder reduced pressure. Recrystallization from acetone/hexane gave16-methylene- 60t-methyl-A -pregnen-1704-01-3,ZO-dione.

By repeating this procedure using the remaining 16- methylene-1704-olsprepared as described in Example XIX hereinabove, the corresponding604-substituted-A -3-ones, namely,

604-fiuoro-16-methylcne-A -pregnen1704-01-3 ,ZO-dione,604-chloro-16-methylene-A -pregnen-l704-ol-3,20-dione, 16-methy'lene- 604-me thyl- 19-nor-A -p re gnen 1704-ol-3,2O-dione,604-flu0ro-16-methylene-19-nor-A -pregnen- 1704-ol-3,20-dione,604-chloro-16-rnethylene-l9-nor-A -pregnen- 1704-ol-3,20-dione,21-fluoro-16-n1ethylene-604-methyl-A -pregnen- 1704-ol-3,2O-dione,604,2l-d-ifluoro-16-methylene-A -pregnen- 174z-ol-3,2O-dione,604-chloro-21-fiuoro- 1 fi-methylene-M-pregnen- 1704-ol-3,2O-dione,

1 21-fluoro-l6-methylene-6a-methyl-l9-nor-A -pregnen- 17oc-Ol-3,ZO-dione, 6a,2l-difiuoro-16-methylene-l9-nor-A pregnen- 1704-01-3,20-dione, 6oc-ChlOIO-2 l-fluoro-16-methylene-19-nor-Apregnen-l7a-ol-3,20-dione, 21-fluoro-16-methylene-6a-methyl-19-nor-A-pregnen- 17rx-0l-3 ,ZO-dione, 21-chloro-6a-fluoro-16-methylene-A-pregnen- 17oc-Ol3,20-di01'1, 60:,2 l-dichloro-16-methylene-A -pregnen-17a-ol-3 ,20-dione, 2 l-chloro-l6-methylene-6a-methyl-19-nor-Apregnen-17a-ol-3,20-dione, 2l-chloro-6a-fluoro-16-methylene-19-nor-Apregnen-I7oc-0l-3,20-di0f16, and 641,2 l-dichloro- 16-methylene-19-nor-A pregnen-17u-ol-3 ,20-dione,

respectively, were obtained.

EXAMPLE XXI The 6u-substituted-A -3-ones prepared as described inExample XX hereinabove were treated with a mixture of acetic acid andacetic anhydride in the presence of p-toluenesulfonic acid, and thenwith methanolic potassium hydroxide, in the manner described in ExampleVII hereinabove, thus giving the corresponding 17-acetates.

EXAMPLE XXII A solution of 1 gram of 16-methylene-A-pregnen-17aol-3,20-dione 17-acetate in 5 cc. of glacial acetic acidcontaining 1 cc. of ethanidithiol was admixed with 1 cc. of borontrifiuoride etherate, and the resulting reaction mixture was allowed tostand at room temperature for 1 'hour. Following this reaction periodthe reaction mixture was cooled in ice to complete the precipitation ofthe dithioketal, then filtered. The filtered precipitate was washed withmethanol until the washings were free of the odor of ethanedithiol, thenrecrystallized from chloroform/methanol to give3-cycloethylenedithio-6-methylene-A -pregnen-l7a-ol-20-one 17-acetate.

A solution of 1 gram of the thus-prepared 3-dithioketal in a mixture of50 cc. of ethanol and 50 cc. of dioxane (the solvents having beendistilled from Raney nickel) was admixed with 20 grams of freshlyprepared Raney nickel, and the resulting reaction mixture was thenrefluxed for 4 hours. Following this reaction period the reactionmixture was cooled to room temperature and then filtered to remove theRaney nickel, which was then washed with hot ethanol and the washingsadded to the filtrate. The filtrate was then evaporated to dryness underreduced pressure, and the resulting residue was dissolved in chloroform.This solution was washed with a dilute, aqueous hydrochloric acidsolution, then with an aqueous sodium carbonate solution and finallywith water until neutral, then dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. Recrystallization of theresulting residue from acetone/hexane gave 16-methylene-A-pregnen-17u-ol-20- one 17-acetate.

By repeating this procedure using the 17-propionate, -caproate and-enathate of 16-methylene-A -pregnen- 17OL-OI-3,20-dIOI1e, prepared asdescribed in Example VII hereinabove, as the steroid starting materials,the 17- propionate, -caproate and -enanthate of l6-methylene- A-pregnan-17a-ol-20-one were obtained.

This procedure was again repeated using the remaining1G-methylene-17a-acetoxy-A -3-ones prepared as described in Examples VIIand XXI hereinabove as the steroid starting materials. In each case thecorresponding 3-dithioketal and then the 3-desoxy steroid, namely,

21-fluoro-1G-methylene-N-pregnen-17a-ol-20-one 17-acetate,

21-chlor0-l6-rnethylene-A -pregnen-l7a-ol-20-one 17-acetate,16-methylene-l9-nor-A -pregnen-17a-ol-20-one 17-acetate,21-fiuoro-16-methylene-19-nor-A -pregnen-17a-ol-2O-one 17-acetate,21-chloro-16-methylene-19-nor-A -pregnen-17a-ol-20-one 17-acetate,16-methylene-6u-methyl-A pregnen-17a-ol-20-one 17-acetate,6a-fiuoro-16-methylene-A -pregnen-17x-ol-20-one 17-acetate,6a-chloro-16-methylene-A -pregnen-17u-ol-20-one 17-acetate,16-methylene-6a-methyl-19-nor-A -pregnen-l7a-ol-20- one 17-acetate,6a-fluoro-16-methylene-l9-nor-A -pregnen-l7a-ol-20-one 17-acetate,6a-chloro-1G-methylene-l9-nor-A -pregnen-l7a-ol-2O-one 17-acetate,2l-fluoro-l6-methylene-6a-methyl-A -pregnen-17a-0l-2O- one 17-acetate,6a,2l-difluoro-l6-methylene-A -pregnen-17a-ol-20-one 17-acetate,6a-chloro-21-fluoro-16-methylene-A -pregnen-17a-ol-20- one 17-acetate,21-fluoro-16-methylene-6a-methyl-19-nor-A -pregnenl7a-ol-20-one17-acetate, 6a,2l-difluoro-16-methylene-19-n0r-A -pregnen-1711-01-20-one 17-acetate, 6a-chloro-21-fluoro-lG-methylene-19=nor-A -pregnen-17a-ol-20-one 17-acetate, 2l-ohloro-16-methylene-6ot-methyl-A-pregnen-17a-ol- 20-one 17-acetate, 21-chloro-6a-fiuoro-16-methylene-A-pregnen-l7u-ol-20- one 17-acctate, 6a,21-dichloro-16-methylene-A-pregnen-17a-ol-2O-one 17-acetate,2l-chloro-16-methylene-6a-methyl-19-nor-A -pregnen- 17a-ol-20-onel7-acetate, 2l-chlor0-6u-fluor 0-1G-mythylene-19-nor-A-prcgnenl7a-ol-20-one 17-acetate, and6a,2l-dichloro-16-methylene-19-nor-A -pregnen-17aol-20-onc l7-acetate,

respectively, was obtained.

Similarly, by again repeating this procedure using the16-methylene-17a-hydroxy-A -3-ones prepared as described in Examples VIand XX hereinabove as the steroid starting materials, the correspondingfree 17u-hydroxy-3- dithioketals and then the free 17a-hydroxy-3-desoxysteroids corresponding to the above-listed 17-acetates were prepared.

EXAMPLE XXIII A solution of 0.17 gram of potassium hydroxide in 0.2 cc.of water and 2.5 cc. of methanol was added over a 30 minute period to aboiling solution of 1 gram of 16- methylene-A -pregnen-17a-ol-20'onel7-acetate in 30 cc. of methanol, maintained under an inert nitrogenatmosphere, and the resulting reaction mixture was boiled for 2 hoursmore following this addition. Next, the reaction mixture was cooled,neutralized with acetic acid and then concentrated under reducedpressure. The thus-obtained concentrate was then diluted with water, andthe resulting precipitate was collected by filtration, washed with waterand dried. Recrystallization from acetone/hexane gave 16-methylene-A-pregnen-17a-ol-20-one.

By repeating this procedure using the remaining 3- desoxy-17a-acetoxysteroids prepared as described in Example XXII hereinabove as thesteroid starting materials, the corresponding 3-desoxy-l7a-hydroxysteroids, identical to those prepared from the corresponding16-methylene-17a-hydroxy-3-ones, were obtained.

17 EXAMPLE XXIV A mixture of 1 gram of l6-methylene-A-pregnen-17aol-3,20-dione 17-acetate, 2 grams of chloranil and 50 cc. oft-butanol was refluxed for 8 hours. Following this reaction period thereaction mixture was cooled, unreacted chloranil was removed therefromby filtration and washed several times with ethyl acetate, and thesewashings were then added to the filtrate. The combined organic solution(filtrate plus washings) was Washed with a cold, aqueous 10% sodiumhydroxide solution until the washings were colorless, and the organiclayer (chiefly ethyl acetate, containing the product) was dried overanhydrous sodium sulfate and evaporated to dryness under reducedpressure. The resulting dry residue was dissolved in methylenedichloride/diethyl ether, decolorized with alumina, and thencrystallized to give 16-methylene-A pregnadien-l7a-ol-3,20-dione17-acetate.

By repeating this procedure using the remaining 16-methylene-l7a-acetoxy-A -3-ones prepared as described in Examples VIIand XXI hereinabove, the corresponding G-dehydro steroids were obtained.

EXAMPLE XXV The procedure of Example XXII hereinabove was repeated usingthe 6-dehydro steroids prepared as described in Example XXIVhereinabove. In each case, the corresponding 3-desoxy-A -17a-acetoxysteroid, namely, 16-methylene-A -pregnadien-l7a-ol-20-one 17-acetate,

2 l-fluoro- 16-methylene-A -pregnadien-17a-o1-20-one 17-acetate, 2l-chlorol 6-methylene-A -pregnadienl7a-01-20-0I16 17-acetate,16-methylene-19-nor-A -pregnadien-17a-ol-20-one l7-acetate,Zl-fiuoro-l6-methylene-19-nor-A -pregnadien-l7a-ol- 20-one l7-acetate,21-chloro-16-methylene-19-nor-A aperegnadien-17a-ol- 20-one 17-acetate,1-nrethylene-6-methyl-A -pregnadien-l7a-ol-20-one l7-acetate,6-fluoro-16-methylene-A -pregnadien-17a-ol-20-one 17-acetate,6-chloro-l6methylene-A -pregnadien-17a-ol-20-one l7-acetate,16-methylene-6-methyl-19-nor-A -pregnadien-l7u-ol- 20-one 17-acetate,6-fluoro-16-methylene-19-nor-A pregnadien-l7a-ol- 20 -one 17-acetate,6-chloro-l6-rnethylene-l9-nor-A -pregnadien-17u-ol- 20-one 17 acetate,6-chloro-16-methylene-19-nor-A -pregnadien-17o -o1- 20'-one l7 acetate,6,2l-difluoro-16-methylene-A -pregnadien-1704-01-20- one l7-acetate,6-chloro-21-fluoro-l6-methylene-A -pregnadien-17a-ol- 20-one 17-acetate,21-fluoro-l6-methylene-6-methyl-19-nor-A -pregnadien-17a-ol-20-one17-acetate, 6,21-difiuoro-16-methylene-19-nor-A -pregnadien-17al-20-one17-ace-tate, 6-chloro-2l-fluoro-l6-methylene-19-nor-A -pregnadien-17a-ol-20-one 17-acetate, 21-chloro-16-methylene-6-methyl-A-pregnadien-17aol-20'-one l7-acetate, 2l-chloro-6-fiuoro-l6-methylene-A-pregn-adien17ozol-20-one 17-acetate, 6,21-dichloro-16-methylene-A-pregnadien-1701-01-20- one l7-acetate,

2 l-chlorol 6-methylene-6-methyl-l9-nor-A pregnadien-17a-ol- 20-one17-a-cetate,

2l-chloro-6-fiuoro-16-methylene-19-nor-A -pregnadien- 17a-ol-20-one17-acetate, and

6,2 l-dichloro-l 6-rnethylene-19-n0r-A -pregnadien-17aol-20-one l7acetate,

respectively, was obtained.

18 EXAMPLE XXVI The procedure of Example XXIII hereinabove was repeatedusing the 3-desoxy-A -17a-acetoxy steroids prepared as described inExample XXV hereinabove as the steroid starting materials. In each case,the corresponding 3-desoxy-A -17a-hydroxy steroid was obtained.

EXAMPLE XXVII The procedure of Example VII hereinabove was repeatedusing the 3-desoxy-A -l7a-ols and 3-desoxy-A 17u-ols prepared asdescribed in Examples XXII and XXVI, respectively, as the steroidstarting materials and mixtures of propionic acid and propionicanhydride, caproic acid and caproic anhydride, and enanthic acid andenanthic anhydride, respectively, as the acylating agents. In each case,the corresponding 17-propionate, -caproate and -enanthate was obtained.

EXAMPLE XXVIII The 6-unsubstituted-A -3-ones prepared as described inExample XXIV hereinabove were epoxidized in the manner described inExample IX hereinabove, thus giving the corresponding 6a,7u-oxidosteroids, namely,

16-methylene-6u,7a-oxido-A -pregnen-l7a-o1-3,20-dione 17-acetate,

2l-fluoro-16-methylene-6a,7a-oxido-A -pregnen-17a-ol- 3,20dione=17-acetate,

2l-chloro-16-methylene-6a,7a-oxido-A -pregnen-17a-ol- 3,20-dione17-acetate,

16-methylene-19-nor-6a,7a-oxido-A -pregnen-17a-ol-3 ,20-

dione 17-acetate,

21-fiuoro-16-methylene-l9-nor-6u,7a-oxido-A -pregneul7u-0l-3,20-di011617-acetate, and

21-chloro-16-methylene-19-nor-6a,7u-oxido-A -pregnenl7a-ol-3,20-dionel7-acetate,

respectively.

EXAMPLE XXIX The 6oz,7oc-0Xid0 steroids prepared as described in ExampleXXVIII hereinabove were reacted with boron trifiuoride in a mixture ofdiethyl ether and benzene in the manner described in Example XIIhereinabove, thus giving the corresponding 6fl-fluoro-7a-hydroxysteroids, namely,

6,8-fiuoro-16-methylene-A -pregnen-7a,17adiol-3,20-dione l7-acetate,

6,8,21-difiuoro-l 6-methylene-A -pregnene-7ot, l7a-diol- 3,20-dione17-acetate,

2l-chloro-Gfl-fiuoro-l6-rnethylene-A -pregnene-7a,17a-

diol-3,20-dione 17-acetate,

6fl-fiuoro-1 6-methylene-19-nor-A -pregnene-7oc,17u-di01- 3,20-di0nel7-acetate,

6B,21-difiuoro-IG-methylene-19-nor-A -pregnene-7a,17a-

diol-3,20-dione 17-acetate, and

respectively.

EXAMPLE XXX One gram of 6,8-fluoro-lfi-methylene-A -pregnene-7oz,17oc-diOl-3,20-di0ll6 l7-acetate was suspended in 35 cc. of glacialacetic acid, and a slow current of anhydrous hydrogen chloride gas waspassed through this suspension for 5 hours. Following this reactionperiod the reaction mixture was concentrated to about one-third of itsinitial volume by distillation under reduced pressure at 35 C., and thenpoured into ice water. The resulting precipitate was collected byfiltration, washed with Water until neutral, and then dried.Recrystallization from methylene dichloride/hexane gave6-fiuoro-l6-methylene-A pregnadien-17a-ol-3,2'0-di0ne l7-acetate,identical to that prepared as described in Example XXIV hereinabove.

By repeating this procedure using the remaining 65- fluoro-7a-hydroxysteroids prepared as described in Example XXIX hereinabove as thesteroid starting materials, the corresponding 6-fiuoro-6-dehydrosteroids, namely,

6,2l-difiuoro-l6-methy1ene-A -pregnadien-17u-ol-3,20-

dione 17-acetate,

21-chloro-6-fluoro-16-methylene-A -pregnadien-17mol-3,20-dione17-acetate,

6-fluoro-l6-methylene-19-nor-A -pregnadien-17a-ol- 3,20-dionel7-acetate,

6,2l-difluoro-16-methylene-l9-nor-A -pregnadien-17o:-

ol-3,20-dione 17-acetate, and

21-chloro-6-fiuoro-16-methylene-19-nor-A -pregnadienl7a-ol-3,20-di0nel7-acetate,

respectively, identical to those prepared as described in Example XXIVhereinabove, Were obtained.

This procedure was again repeated using the 60:,7uoxido steroidsprepared as described in Example XXVIII hereinabove as the steroidstarting materials. In each case, the corresponding 6-chloro-6-dehydrosteroid, namely,

respectively, identical to that prepared as described in Example XXIVhereinabove, was obtained.

It will be obvious to those skilled in the art that other changes andvariations can be made in carrying out the present invention withoutdeparting from the spirit and scope thereof as defined in the appendedclaims.

I claim:

1. A compound represented by the general formula:

CHzR

wherein R is selected from the group consisting of hydrogen and methyl,R is selected from the group consist ing of hydrogen, fluorine andchlorine, R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group containing less than 12 carbon atoms,

20 R is selected from the group consisting of hydrogen, methyl, fluorineand chlorine, and Z is selected from the group consisting of a doublebond and a saturated linkage between the carbon atoms at the 6- and7-positions.

2. 16-trnethylene-A -pregnen-l7a-ol-20-one.

3. 16-methylene-19-nor-A -pregnen-17a-ol-20-one.

4. l6-methylene-6a-methyl-A -pregnen-17a-ol-20-0ne.

5. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of16-methylene-6u-methyl-A -pregnen-17aol-20-one.

6. 16-methylene-6a-methyl 19-nor-A -pregnen col-20-one.

7. 6a-halo 16-methylene-A -pregnen 17m-ol-20-one wherein the halogen hasan atomic number less than 35.

8. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of6a-halo-1G-methyIene-M-pregnen-l7u-ol- 20-one wherein the halogen has anatomic number less than 35.

9. 6a-halo-l6-methylene-l9-nor-A -pregnen 1711-01-20- one wherein thehalogen has an atomic number less than 35.

10. l6-methylene-A -pregnadien-17a-ol-20-one.

11. 16-methylene-19-nor-A -pregnadien-17a-ol-20-one.

12. 16-metihylene-6methyl-A -pregnadien 1711-01-20- one.

13. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of'16-methylene-6-methyl-A -pregnadien- 17a-ol-20-one.

14. 16-methylene-6-methyl-19-nor-A -pregnadien47aol-20-one.

15. 6 halo-16-methylene-A pregnadien 17u-ol-20- one wherein the halogenhas an atomic number less than 35.

16. A hydrocarbon carboxylic acid ester of less than 12 carbon atoms of6-halo-16-methy lene-A npregnadien-17ao'l-20-one wherein the halogen hasan atomic number less than 35 17. 6-ha1lo-16-methylene 19-nor-A-pregnadien-17aol-20-one wherein the halogen has an atomic number lessthan 35.

18. 21-h-alo 16-methylene-M-pregnen 17oc-Ol-20-On6 wherein the halogenhas an atomic number less than 35.

19. 21-halo-16-methylene-A -pregnadiene 1711-01-20- one wherein thehalogen has an atomic number less than 35.

20. 6a,21-diha'lo 16-methylene-A pregnen-l7a ol-20- o151e wherein thehalogen has an atomic number less than 3 21. 6,2l-dilralo l6-methylene-A-pregnadien-17a-ol- 20-one wherein the halogen has an atomic number lessthan 35.

References Cited by the Examiner UNITED STATES PATENTS 3,186,985 6/1965Robinson 260239.5i

ELBERT L. ROBERTS, Acting Primary Examin T. M. MESHBESHER, AssistantExaminer.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,284,476 November 8, 1966 Fred A. Kincl It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 3, line 57, for "mixture" read mixtures column 13, line 61, for"6B,21difluoro-l6-methylene19- norpregnane-SB,5d-trio1-20-one" read6B,21-dichloro- 16B-methy1-16u,17a-oxidopregnane-3B,Sddio120-one I a L+column 14, line 61, for "6dfluoro-16-methy1ene-A qpregnenl7aol3,20dione" read 6af1uoro-16-methy1ene-A Pregnen-l7a-Ol-3,ZO-dioneline 63, for "16-methylene-6amethy1-19-nor-A pregnen" read16-methy1ene-6a-methy1- l9-norA -pregnencolumn 15, line 1, for"21-f1uoro-16- methylene-6amethy119-nor-A -pregnen-" read21-fluorol6-methylene-6amethy1-19-nor-A pregnen line 7, for"21fluoro-l6-methy1ene-6amethyl19-nor-A -pregnen-" read21-ch1orol6-methylene6omethyl-A pregnenline 33, for "ethanidithiol readethanedithiol column 17, between lines 52 and S3, insert21fluoro-l6-methylene-6- methyl-A -pregnadien-l7q-ol-20-one 17-acetateSigned and sealed this 12th day of September 1967.

(SEAL) Attest:

I ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND REPRESENTED BY THE GENERAL FORMULA: 6-R3,6 AND7-(Z-),10-R,16-(CH2=),17-(R1-CH2-CO-), 17-(R2-O-)-4-ESTRENE WHEREIN R ISSELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND METHYL, R'' ISSELECTED FROM THE GROUP CONSISTING OF HYDROGEN, FLUORINE AND CHLORINE,R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND A HYDROCARBONCARBOXYLIC ACYL GROUP CONTAINING LESS THAN 12 CARBON ATOMS, R3 ISSELECTED FROM THE GROUP CONSISTING OF HYDROGEN, METHYL, FLUORINE ANDCHLORINE, AND Z IS SELECTED FROM THE GROUP CONSISTNG OF A DOUBLE BONDAND A SATURATED LINAKGE BETWEEN THE CARBON ATOMS AT THE 6- AND7-POSITIONS.
 2. 15-METHYLENE$4-PREGNEN-17A-OL-20-ONE.